Predicting developmental dysplasia of the hip in at-risk newborns.

BACKGROUND: The development of developmental dysplasia of the hip can be attributed to several risk factors and often in combination with each other. When predicting the likelihood of developing this condition, clinicians tend to over and underestimate its likelihood of occurring. Therefore, the study aim is to determine among at-risk newborns how to best predict developmental dysplasia of the hip (DDH) within 8 weeks post-partum. METHODS: Prospective cohort study in secondary care. Patient population included newborns at-risk for DDH - we assessed 13,276 consecutive newborns for the presence of DDH risk factors. Only newborns with at least one of the predefined risk factors and those showing an abnormal examination of the hip were enrolled (n = 2191). For the development of a risk prediction model we considered 9 candidate predictors and other variables readily available at childbirth. The main outcome measure was ultrasonography at a median age of 8 weeks using consensus diagnostic criteria; outcome assessors were blinded. RESULTS: The risk model includes four predictors: female sex (OR = 5.6; 95% CI: 2.9-10.9; P  4000 g (OR = 1.6; 95% CI: 0.6-4.2; P = 0.34), and abnormal examination of hip (OR = 58.8; 95% CI: 31.9, 108.5; P <  0.001). This model demonstrated excellent discrimination (C statistic = 0.9) and calibration of observed and predicted risk (P = 0.35). A model without the variable 'hip examination' demonstrated similar performance. CONCLUSION: The risk model quantifies absolute risk of DDH within 8 weeks postpartum in at-risk newborns. Based on clinical variables readily available at the point of childbirth, the model will enhance parental counselling and could serve as the basis for real time decisions prior to discharge from maternity wards

Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity

Aquaglyceroporins (AQPs) transport water and glycerol and play important roles in drug-uptake in pathogenic trypanosomatids. For example, AQP2 in the human-infectious African trypanosome, Trypanosoma brucei gambiense, is responsible for melarsoprol and pentamidine-uptake, and melarsoprol treatment-failure has been found to be due to AQP2-defects in these parasites. To further probe the roles of these transporters, we assembled a T. b. brucei strain lacking all three AQP-genes. Triple-null aqp1-2-3 T. b. brucei displayed only a very moderate growth defect in vitro, established infections in mice and recovered effectively from hypotonic-shock. The aqp1-2-3 trypanosomes did, however, display glycerol uptake and efflux defects. They failed to accumulate glycerol or to utilise glycerol as a carbon-source and displayed increased sensitivity to salicylhydroxamic acid (SHAM), octyl gallate or propyl gallate; these inhibitors of trypanosome alternative oxidase (TAO) can increase intracellular glycerol to toxic levels. Notably, disruption of AQP2 alone generated cells with glycerol transport defects. Consistent with these findings, AQP2-defective, melarsoprol-resistant clinical isolates were sensitive to the TAO inhibitors, SHAM, propyl gallate and ascofuranone, relative to melarsoprol-sensitive reference strains. We conclude that African trypanosome AQPs are dispensable for viability and osmoregulation but they make important contributions to drug-uptake, glycerol-transport and respiratory-inhibitor sensitivity. We also discuss how the AQP-dependent inverse sensitivity to melarsoprol and respiratory inhibitors described here might be exploited

The chemical characterization of Nigerian propolis samples and their activity against Trypanosoma brucei.

Profiling of extracts from twelve propolis samples collected from eight regions in Nigeria was carried out using high performance liquid chromatography (LC) coupled with evaporative light scattering (ELSD), ultraviolet detection (UV) and mass spectrometry (MS), gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR). Principal component analysis (PCA) of the processed LC-MS data demonstrated the varying chemical composition of the samples. Most of the samples were active against Trypanosoma b.brucei with the highest activity being in the samples from Southern Nigeria. The more active samples were fractionated in order to isolate the component(s) responsible for their activity using medium pressure liquid chromatography (MPLC). Three xanthones, 1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl)xanthone, 1,3,7-trihydroxy-4,8-di-(3-methylbut-2-enyl)xanthone a previously undescribed xanthone and three triterpenes: ambonic acid, mangiferonic acid and a mixture of α-amyrin with mangiferonic acid (1:3) were isolated and characterised by NMR and LC-MS. These compounds all displayed strong inhibitory activity against T.b.brucei but none of them had higher activity than the crude extracts. Partial least squares (PLS) modelling of the anti-trypanosomal activity of the sample extracts using the LC-MS data indicated that high activity in the extracts, as judged from LCMS 2data, could be correlated to denticulatain isomers in the extracts

Instability of aquaglyceroporin (Aqp) 2 contributes to drug resistance in trypanosoma brucei

Defining mode of action is vital for both developing new drugs and predicting potential resistance mechanisms. Sensitivity of African trypanosomes to pentamidine and melarsoprol is predominantly mediated by aquaglyceroporin 2 (TbAQP2), a channel associated with water/glycerol transport. TbAQP2 is expressed at the flagellar pocket membrane and chimerisation with TbAQP3 renders parasites resistant to both drugs. Two models for how TbAQP2 mediates pentamidine sensitivity have emerged; that TbAQP2 mediates pentamidine translocation across the plasma membrane or via binding to TbAQP2, with subsequent endocytosis and presumably transport across the endosomal/lysosomal membrane, but as trafficking and regulation of TbAQPs is uncharacterised this remains unresolved. We demonstrate that TbAQP2 is organised as a high order complex, is ubiquitylated and is transported to the lysosome. Unexpectedly, mutation of potential ubiquitin conjugation sites, i.e. cytoplasmic-oriented lysine residues, reduced folding and tetramerization efficiency and triggered ER retention. Moreover, TbAQP2/TbAQP3 chimerisation, as observed in pentamidine-resistant parasites, also leads to impaired oligomerisation, mislocalisation and increased turnover. These data suggest that TbAQP2 stability is highly sensitive to mutation and that instability contributes towards the emergence of drug resistance

Comparative genomics of drug resistance in <i>Trypanosoma brucei rhodesiense</i>

Trypanosoma brucei rhodesiense is one of the causative agents of human sleeping sickness, a fatal disease that is transmitted by tsetse flies and restricted to Sub-Saharan Africa. Here we investigate two independent lines of T. b. rhodesiense that have been selected with the drugs melarsoprol and pentamidine over the course of 2 years, until they exhibited stable cross-resistance to an unprecedented degree. We apply comparative genomics and transcriptomics to identify the underlying mutations. Only few mutations have become fixed during selection. Three genes were affected by mutations in both lines: the aminopurine transporter AT1, the aquaporin AQP2, and the RNA-binding protein UBP1. The melarsoprol-selected line carried a large deletion including the adenosine transporter gene AT1, whereas the pentamidine-selected line carried a heterozygous point mutation in AT1, G430R, which rendered the transporter non-functional. Both resistant lines had lost AQP2, and both lines carried the same point mutation, R131L, in the RNA-binding motif of UBP1. The finding that concomitant deletion of the known resistance genes AT1 and AQP2 in T. b. brucei failed to phenocopy the high levels of resistance of the T. b. rhodesiense mutants indicated a possible role of UBP1 in melarsoprol-pentamidine cross-resistance. However, homozygous in situ expression of UBP1-Leu(131) in T. b. brucei did not affect the sensitivity to melarsoprol or pentamidine

Experiences of mental illness stigma, prejudice and discrimination: A review of measures

Background: There has been a substantial increase in research on mental illness related stigma over the past 10 years, with many measures in use. This study aims to review current practice in the survey measurement of mental illness stigma, prejudice and discrimination experienced by people who have personal experience of mental illness. We will identify measures used, their characteristics and psychometric properties. Method. A narrative literature review of survey measures of mental illness stigma was conducted. The databases Medline, PsychInfo and the British Nursing Index were searched for the period 1990-2009. Results: 57 studies were included in the review. 14 survey measures of mental illness stigma were identified. Seven of the located measures addressed aspects of perceived stigma, 10 aspects of experienced stigma and 5 aspects of self-stigma. Of the identified studies, 79% used one of the measures of perceived stigma, 46% one of the measures of experienced stigma and 33% one of the measures of self-stigma. All measures presented some information on psychometric properties. Conclusions: The review was structured by considering perceived, experienced and self stigma as separate but related constructs. It provides a resource to aid researchers in selecting the measure of mental illness stigma which is most appropriate to their purpose. © 2010 Brohan et al; licensee BioMed Central Ltd

A predictive model for the early identification of patients at risk for a prolonged intensive care unit length of stay

<p>Abstract</p> <p>Background</p> <p>Patients with a prolonged intensive care unit (ICU) length of stay account for a disproportionate amount of resource use. Early identification of patients at risk for a prolonged length of stay can lead to quality enhancements that reduce ICU stay. This study developed and validated a model that identifies patients at risk for a prolonged ICU stay.</p> <p>Methods</p> <p>We performed a retrospective cohort study of 343,555 admissions to 83 ICUs in 31 U.S. hospitals from 2002-2007. We examined the distribution of ICU length of stay to identify a threshold where clinicians might be concerned about a prolonged stay; this resulted in choosing a 5-day cut-point. From patients remaining in the ICU on day 5 we developed a multivariable regression model that predicted remaining ICU stay. Predictor variables included information gathered at admission, day 1, and ICU day 5. Data from 12,640 admissions during 2002-2005 were used to develop the model, and the remaining 12,904 admissions to internally validate the model. Finally, we used data on 11,903 admissions during 2006-2007 to externally validate the model.</p> <p>Results</p> <p>The variables that had the greatest impact on remaining ICU length of stay were those measured on day 5, not at admission or during day 1. Mechanical ventilation, PaO₂: FiO₂ratio, other physiologic components, and sedation on day 5 accounted for 81.6% of the variation in predicted remaining ICU stay. In the external validation set observed ICU stay was 11.99 days and predicted total ICU stay (5 days + day 5 predicted remaining stay) was 11.62 days, a difference of 8.7 hours. For the same patients, the difference between mean observed and mean predicted ICU stay using the APACHE day 1 model was 149.3 hours. The new model's r²was 20.2% across individuals and 44.3% across units.</p> <p>Conclusions</p> <p>A model that uses patient data from ICU days 1 and 5 accurately predicts a prolonged ICU stay. These predictions are more accurate than those based on ICU day 1 data alone. The model can be used to benchmark ICU performance and to alert physicians to explore care alternatives aimed at reducing ICU stay.</p